Cancer immunotherapies that exploit ex vivo manipulation of a patient's own cells can generate significant anti- tumor immune responses, but present significant practical limitations. Nanoparticle-based antigen presenting systems provide an alternative approach to generate anti-tumor responses without ex vivo cell manipulation, but the defined antigens will likely need to be personalized to each patient. We have demonstrated a new concept, the use of implantable biomaterials that can localize large numbers of dendritic cells (DCs) from the host, and efficiently activate these cells while loading with antigens derived from a tumor biopsy. This approach demonstrated unprecedented ability to promote regression of established tumors in several pre- clinical models, and we have recently initiated a Phase I trial of this new approach to treat stage IV melanoma patients. However, the antigen in this vaccine is derived from a biopsy, leading to the requirement that each vaccine be manufactured for a specific patient, and the vaccine requires surgical implantation. This project is based on the premise that combining delivery of traditional chemotherapeutic agents and biomaterial- based vaccination will lead to therapeutic immune responses, by generating patient-specific antigen in situ, obviating the need to identify or load antigen onto vaccines prior to placement in the body. Our hypothesis will be tested using the following Aims: (1) Develop cryogels capable of being injected intra and/or peritumorally that recruit DCs through GM-CSF release, and control the timing of release of nanoparticles (NPs) containing toll like receptor ligands from the biomaterial vaccine in order to concentrate and activate DCs within the tumor, and enhance their trafficking to the draining lymph node. (2) Determine the impact of an approach to localize immunostimulatory chemotherapeutic agents to tumors on cancer cell death, and determine the impact of combined chemotherapy and vaccination on tumor growth and the tumor-specific host immune response. (3) Examine the ability of vaccination at the primary tumor to yield therapeutic effects on distant tumors in the body, and combine the biomaterial-based vaccine strategy with checkpoint blockade therapy. These studies will utilize both transplantable tumor models and a transgenic melanoma model. This project will result in the development of a new, patient-specific vaccination strategy that does not require personalized manufacturing. We expect this vaccine strategy will synergize with checkpoint blockade therapy, yielding robust and systemic therapeutic benefit.